To fulfill the promise of regenerative medicine in the lung, it will be necessary to identify and characterize the cell lineages that affect postnatal lung epithelial repair and to effectively control their maintenance, expansion, and differentiation into mature and functional epithelial cells. Asthma and COPD are chronic lung diseases which affect the bronchiolar ainways of the lung and are leading causes of morbidity and mortality. Both diseases are thought to involve a chronic injury-repair-improper regeneration cycle that leads to the eventual breakdown of normal airway structure and function leading to loss of respiratory function. We hypothesize that epithelial progenitors within the bronchiolar airways and the pathways that regulate their expansion and differentiation are critical for proper ain/vay repair and regeneration after both chronic and acute lung injury that occurs in lung diseases such as asthma and COPD. Given the immense clinical burden imposed by asthma and COPD, we believe a focus on repair and regeneration of bronchiolar epithelium will have a significant and direct impact on human health. Moreover, a focus on pathways that can be modulated using small molecule or druggable approaches would be beneficial for directly translating basic research findings to human therapy. We propose to leverage decades of experience by leading experts in lung development, stem cell biology, and pulmonary medicine to collaboratively harness novel technologies for expansion and differentiation of endogenous lung progenitors as well as those derived from induced pluripotent stem cells (iPSCs). By focusing on new findings in the investigators laboratories involving the epigenetie regulation of bronchiolar epithelial progenitors as well as novel techniques for generation of iPSCs, the Penn component ofthe Lung Repair and Regeneration Consortium (PennLRRC) will dramatically advance the field towards the ultimate goal of generating clinically relevant therapies for promoting lung repair and regeneration. The underlying thesis of the PennLRRC Consortium is that a sophisticated understanding of basic epigenetie mechanisms involving miRNA and Hdac pathways will be critical to optimally manipulate in vivo or generate ex vivo lung progenitors and their derivatives for clinical use. RELEVANCE (See instructions): We will explore the roles for miRNA and Hdac pathways in lung regeneration and development as well as in the generation and differentitation of iPSCs for use in regenerative therapies in the lung. Since small molecule modulators of miRNA and Hdac pathways exist, we believe that investigation into how these pathways regulate lung regeneration will have an important impact on the development of new therapies for lung disease